The present invention relates to inhibiting a T cell response to an alloantigen and further relates to inhibiting and/or preventing reactivation of previously activated T cells. More particularly, the present invention relates to the field of preventing, reducing or treating an immune response caused by immune effector cells to foreign tissue and/or cells and/or organs. The invention further relates to preventing, reducing or treating transplant rejection and/or graft versus host reaction.
Tolerance is the acquired lack of specific responsiveness to an antigen to which an immune response would normally occur. Typically, to induce tolerance, there must be an exposure to a tolerizing antigen, which results in the death or functional inactivation of certain lymphocytes. Complete tolerance is characterized by the lack of a detectable immune response, to the second antigenic challenge. Partial tolerance is typified by the quantitative reduction of an immune response.
The function of the immune system is to eliminate foreign bodies which may contain pathogens, and to maintain unresponsiveness or tolerance against self antigen. T cell tolerance is achieved 1) in the thymus where thymocytes reactive for self-peptides are eliminated by clonal deletion (central tolerance), and 2) in the periphery by exposure to self-antigens under tolerogenic conditions (peripheral tolerance). Clonal deletion can also result from expression of cell death molecules on antigen presenting cells. Classic examples of death molecules are Fas ligand (FasL) and TRAIL ligand, which ligate their receptors, Fas and DR4, respectively, on activated T cells, inducing apoptosis of the T cells. The interaction of CD27, a member of the TNFR superfamily, and the CD27-ligand (CD70) also induces T cell apoptosis.
Unfortunately, the immune system does not distinguish beneficial intruders, such as transplanted tissue, from those that are harmful, and thus the immune system rejects transplanted tissue or organs. Rejection of transplanted organs is significantly mediated by alloreactive T cells present in the host which recognize donor alloantigens or xenoantigens.
At present, in order to prevent or reduce an immune response against a transplant, patients are treated with powerful immunosuppressive drugs. The infusion of individuals with drugs that prevent or suppress T-cell immune response does inhibit transplant rejection, but can also result in general immune suppression, toxicity and even death due to opportunistic infections. Because of the toxicity and incomplete response rate to conventional treatment of donor tissue rejection, alternative approaches are needed to treat patients who cannot withstand or do not respond to current modes of drug therapy.
Accordingly, there is a need for the prevention and/or reduction of an unwanted immune response by a host to a transplant by immune effector cells as a method to avert host rejection of donor tissue. Also advantageous would be a method to eliminate or reduce an unwanted immune response by a donor tissue against a recipient tissue, known as graft-versus-host disease.
It has been discovered that mesenchymal stem cells can be used in transplantation to ameliorate a response by the immune system such that an immune response to an antigen(s) will be reduced or eliminated.
In accordance with one aspect of the invention, there is provided a method for reducing or suppressing an immune response caused by T cells responding to an alloantigen, in particular allogeneic tissue, organ or cells, wherein the immune response is reduced or suppressed by the use of mesenchymal stem cells. The mesenchymal stem cells may be autologous to the T cells (obtained from the same host) or allogeneic or xenogeneic to the T cells. In the case of mesenchymal stem cells that are allogeneic to the T cells, the mesenchymal stem cells may be autologous to the cells or tissue to which the T cells are responding (obtained from the same host) or the mesenchymal stem cells may be obtained from a host that is allogeneic to both the source of the T cells and the source of the cells or tissue to which the T cells are responding. Alternatively the mesenchymal stem cells can be obtained from a source that is xenogeneic to either or both the source of the T cells and the source of the cells or tissue to which the T cells are responding.
In accordance with another aspect of the present invention there is provided a process for preventing restimulation of activated T cells (activated against an alloantigen, in particular an allogeneic organ, tissue or cells) by contacting activated T cells with mesenchymal stem cells in an amount effective to prevent and/or reduce a subsequent T cell response to a foreign antigen. The mesenchymal stem cells that are used may be autologous to the T cells and/or allogeneic to the T cells. When using allogeneic mesenchymal stem cells, the mesenchymal stem cells may be obtained from the same host as the tissue or cells that activated the T cells or may be obtained from a host that is allogeneic to both the T cells and the host that provided the cells or tissues that activated the T cells.
In accordance with another aspect of the present invention, mesenchymal stem cells are used to suppress or ameliorate an immune response to a transplant (tissue, organ, cells, etc.) by administering to the transplant recipient mesenchymal stem cells in an amount effective to suppress or ameliorate an immune response against the transplant. The mesenchymal stem cells may be autologous to the transplant recipient or may be allogeneic or xenogeneic to the transplant recipient.
Accordingly, one method of the present invention provides contacting the recipient of donor tissue with mesenchymal stem cells. In one embodiment of this aspect, the method involves administering mesenchymal stem cells to the recipient of donor tissue. The mesenchymal stem cells can be administered to the recipient before or at the same time as the transplant or subsequent to the transplant. The mesenchymal stem cells may be autologous or may be allogeneic to the recipient and can be obtained from the donor. In another aspect of the invention, the allogeneic mesenchymal stem cells can also be obtained from a source other than the donor and such source need not be matched either to the donor type or the recipient type.
In a further embodiment of this method, as part of a transplantation procedure the mesenchymal stem cells are modified to express a molecule that induces cell death. The mesenchymal stem cells can be used to deliver to the immune system a molecule that induces apoptosis of activated T cells carrying a receptor for the molecule. This results in the deletion of activated T lymphocytes and in the suppression of an unwanted immune response to a transplant. In accordance with this aspect of the invention, allogeneic mesenchymal stem cells are modified to express a cell death molecule. The molecule can be exogenous or endogenous to the mesenchymal stem cells. In preferred embodiments of the methods described herein, the mesenchymal stem cells express the cell death molecule Fas ligand or TRAIL ligand.
The mesenchymal stem cells can also be administered to the recipient as part of the transplant. To this objective, the present invention provides a method for reducing or ameliorating an immune response by providing to the recipient donor tissue or organ that is perfused with or includes mesenchymal stem cells obtained from the donor of the organ or tissue or mesenchymal stem cells from a third party or mesenchymal stem cells autologous to the T cells. The mesenchymal stem cells ameliorate an immune response by the recipient""s T cells against the foreign tissue when it is transplanted into the recipient.
In a further embodiment of this invention, the mesenchymal stem cells perfused into the organ or tissue also can include a molecule that induces activated T cell death.
In another embodiment, the method of the present invention provides treating a patient who has received a transplant, in order to reduce the severity of or eliminate a rejection episode against the transplant, by administering to the recipient of donor tissue mesenchymal stem cells after the donor tissue has been transplanted into the recipient. The mesenchymal stem cells can be autologous or allogeneic to the recipient. The allogeneic mesenchymal stem cells can be obtained from the donor or from a third party source. The presentation of mesenchymal stem cells to a recipient undergoing an adverse immune response to a transplant induces nonresponsiveness of T cells to further antigenic stimulation thereby reducing or eliminating an adverse response by activated T cells to donor tissue or organ.
In a further aspect of the present invention, there is provided a method of reducing an immune response by donor tissue, organ or cells against a recipient, i.e. graft versus host response, comprising treating the donor tissue, organ or cells with allogeneic (allogeneic to the donor) mesenchymal stem cells ex vivo prior to transplantation of the tissue, organ or cells into the recipient. The mesenchymal stem cells reduce the responsiveness of T cells in the transplant that may be subsequently activated against recipient antigen presenting cells such that the transplant may be introduced into the recipient""s (host""s) body without the occurrence of, or with a reduction in, an adverse response of the transplant to the host. Thus, what is known as xe2x80x9cgraft versus hostxe2x80x9d disease may be averted.
In a preferred embodiment, the donor transplant may be first exposed to recipient or third party tissue or cells ex vivo, to activate the T cells in the donor transplant. The donor transplant is then contacted with mesenchymal stem cells autologous or allogeneic to the donor. The mesenchymal stem cells can be recipient or third party mesenchymal stem cells. The mesenchymal stem cells will reduce or inhibit an adverse secondary immune response by T cells in the donor transplant against antigenic stimulation by the recipient when the donor transplant is subsequently placed into the recipient.
Accordingly, the mesenchymal stem cells can be obtained from the recipient, for example, prior to the transplant. The mesenchymal stem cells can be isolated and stored frozen until needed. The mesenchymal stem cells may also be culture-expanded to desired amounts and stored until needed. The mesenchymal stem cells are administered to the recipient in an amount effective to reduce or eliminate an ongoing adverse immune response caused by the donor transplant against the recipient (host). The presentation of the mesenchymal stem cells to the recipient undergoing an adverse immune response caused by a transplant inhibits the ongoing response and prevents restimulation of the T cells thereby reducing or eliminating an adverse response by activated T cells to recipient tissue.
A further embodiment includes modifying the recipient""s mesenchymal stem cells with a molecule that induces activated T cell death.
Thus, in accordance with preferred embodiments of the present invention, human mesenchymal stem cells are employed to treat transplant rejection and or graft versus host disease as a result of a transplant and or to prevent or reduce transplant rejection and or graft versus host disease. Human mesenchymal stem cells may also be employed to facilitate the use of xenogeneic grafts or transplants. It is also within the present invention to use xenogeneic cells, such as non-human primate cells, for the above purposes.
It has further been discovered that the supernatant derived from MSC cultures and MSC/mixed lymphocyte reaction cultures has a suppressive effect on a T cell response to an alloantigen. Thus the present invention further provides a method of use of supernatants.